Anxiety and mood disorders are debilitating conditions that cause tremendous personal suffering and engender a high societal and economic burden. A central feature of these disorders is excessive anticipation of potentially aversive outcomes. While anticipation is critical for successful preparation and adaptation to aversive events, dysfunction in this system can interfere markedly with social and occupational functioning. By investigating the neurobiology of this anticipatory system, neural areas associated with specific functions of anticipation, such as autonomic processing, negative affect, and behavioral withdrawal, can be identified and targeted by psychological or biological treatments. In addition, the proposed event-related functional magnetic resonance imaging (fMRI) studies capitalize on 2 key characteristics of anticipation: uncertainty about the future and an inability to control it. Building on prior research using an anticipation paradigm with 1 warning symbol that predicts aversive pictures and another predicting neutral, the first study will manipulate uncertainty (i.e., predictability of picture content) by including an ambiguous warning symbol that is followed by either aversive or neutral pictures. The second study will manipulate uncontrollability by including a condition in which a behavioral response can shorten picture duration. The influence of uncertainty and uncontrollability on key neural areas in the proposed model for aversive anticipation will be tested with healthy volunteers in the first 2 studies. For the final study, both paradigms will be used with relevant clinical populations-generalized anxiety disorder, social anxiety disorder (social phobia), and major depressive disorder-to determine how the normative circuitry identified in the first 2 studies is aberrant in anxiety and mood disorders. The primary prediction is that there is a neural signature for anxiety disorders that corresponds to a general dysfunction in anticipatory processes engaged by potential aversive outcomes, especially in situations of uncertainty and uncontrollability. In sum, the emphasis of this application on the capacity to anticipate impending danger is a novel approach to the study of affective disorders that is geared toward basic knowledge about the neurobiology of healthy defense mechanisms (e.g., anticipation that results in adaptive response) as well as understanding how dysfunction in this system occurs.